Axons and dendrites of neurons are long cellular extensions from neurons. The distal tip of an extending axon or neurite comprises a specialized region known as the growth cone, which senses the local environment and guides axonal growth toward the neuron's target cell. The guidance of growth at the cone involves various classes of adhesion molecules, intercellular signals, as well as factors that stimulate and inhibit growth cones.
Nerve cell function is greatly influenced by the contact between the neuron and other cells in its immediate environment. These cells include specialized glial cells, oligodendrocytes in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (PNS), which ensheathe the neuronal axon with myelin (an insulating structure of multi-layered membranes). While CNS neurons have the capacity to regenerate after injury, they are inhibited from doing so because of the presence of inhibitory proteins present in myelin and possibly also by other types of molecules normally found in their local environment (Brittis and Flanagan, Neuron 2001, 30, pp. 11-14; Jones et al., J. Neurosci. 2002, 22, pp. 2792-2803; Grimpe et al., J. Neurosci. 2002, 22, pp. 3144-3160).
Several myelin inhibitory proteins that are found on oligodendrocytes have been characterized, e.g., NogoA (Chen et al., Nature, 2000, 403, 434-439; Grandpre et al., Nature 2000, 403, 439-444), myelin associated glycoprotein (MAG, McKerracher et al., Neuron 1994, 13, 805-811; Mukhopadhyay et al., Neuron 1994, 13, 757-767) and oligodendrocyte glycoprotein (OM-gp, Mikol and Stefansson, J. Cell. Biol. 1988, 106, 1273-1279). Each of these proteins has been separately shown to be a ligand for the neuronal Nogo receptor-1 (“NgR”) (Wang et al., Nature 2002, 417, 941-944; Liu et al., Science, 2002, 297, 1190-93; Grandpre et al., Nature 2000, 403, 439-444; Chen et al., Nature, 2000, 403, 434-439; Domeniconi et al., Neuron, 2002, 35, 283-90). Nogo-66 is a 66 amino acid peptide from NogoA having the ability to inhibit neurite outgrowth and cause growth cone collapse. (Fournier et al., Nature 2001, 409, 341-346). Nogo receptor-1 is a GPI-anchored membrane protein that contains 8 leucine-rich repeats (Fournier et al., Nature 2001, 409, 341-346). Upon interaction with an inhibitory protein (e.g., NogoA, MAG and OM-gp), the Nogo receptor-1 complex transduces signals that lead to growth cone collapse and inhibition of neurite outgrowth.
Axonal damage is a key pathology in many injuries of the central nervous system (CNS), such as spinal cord injury, traumatic brain injury and stroke, as well as in multiple sclerosis (MS). A recently developed strategy for treating CNS injuries and CNS diseases is to interfere with the axonal growth inhibition that occurs through the interaction of myelin proteins with their axonal receptors, such as NgR. For example, the anti-NogoA antibody IN-1 was shown to improve functional recovery in rats that had undergone spinal cord transection. (Lee et al., Nature Reviews 2003, 2, 1-7.) In addition, a 40 residue peptide known as NEP1-40, an antagonist of NogoA, was shown to attenuate the effects of myelin or Nogo-66 on growth cone collapse and neurite outgrowth, and improved the outcome in vivo following spinal cord injury. (Lee et al., Nature Reviews 2003, 2, 1-7.) Although these reagents have shown great promise in treating injuries to the CNS, there remains a need in the art for additional compounds that inhibit NgR signaling and/or attenuate myelin-mediated growth cone collapse and/or inhibit neurite outgrowth inhibition.